The sepsis-induced alterations in carbohydrate and protein metabolism are described in detail, yet the abnormalities in lipid metabolism are poorly understood. The mechanism causing hypertriglyceridemia during sepsis remains unknown. This could result from increased triglyceride production by the liver, reduced peripheral removal by lipoprotein lipase, and/or an increase in liver secretion rate. This study will identify and describe the mechanism(s) responsible for the altered lipid metabolism during gram-negative sepsis. The changes in lipid metabolism will be assessed by measuring in vivo serum lipids, synthesis rates of the lipid classes in liver and adipose tissue, activities of lipoprotein lipase, the liver lipogenic enzymes, rates of triglyceride secretion and clearance, and insulin and glucagon levels in a septic rat model. The role of the liver will be evaluated further by determining in vitro synthesis of the lipid classes in freshly isolated hepatocytes from fasted septic and fasted control rats. To distinguish the effects of food restriction and sepsis on lipid metabolism, lipid synthesis will be measured in isolated hepatocytes from intragastrically-fed rats. The observed abnormalities of lipid synthesis in the isolated hepatocytes will be investigated further by using primary cultures of the isolated hepatocytes. These experiments with the primary culture will define the recovery time of lipid synthesis, the effect of different substrates in the presence or absence of insulin on lipid synthesis, and the presence of extracellular factor(s) by performing cross-over studies. Hepatocytes from normal and septic rats are incubated with septic rat serum and normal serum. The proposed studies will clarify the mechanism of hypertriglyceridemia in sepsis and hopefully serve as a basis for developing better nutritional support for the septic patient.